Genomic imprinting is a form of epigenetic gene regulation that leads to one of the two parental copies of a gene being inherited in a transcriptionally silent state. Mutations within imprinted loci disrupt normal patterns of growth and development, underlying specific cognitive defects and predisposition to certain cancers. The molecular mechanisms by which imprinted genes are programmed to be silent, and how genomic imprints are propagated each generation are not well understood. Insights gained in the study of imprinted gene regulation, however, have been indispensable to the current concept of epigenetic gene regulation in general. A new and somewhat unexpected finding in the field of genomic imprinting is the discovery of a cluster of imprinted genes on the mammalian X chromosome. Unique features about the ontogeny and global control of gene expression on the X suggest that the epigenetic control of X-linked imprinted gene expression may be dramatically different from that of imprinted autosomal genes. The primary goal of the work proposed in this application is to fully characterize the epigenetic regulatory factors that influence transcription of the newly discovered cluster of Xlinked imprinted genes. We will first perform experiments to determine if the regulation of Xlinked imprinted genes is influenced by X chromosome inactivation and DNA methylation. We will then perform chromatin immunoprecipitation experiments using microarray technology to determine the factors that regulate expression at this locus. Finally, we will produce mutant mice by gene targeting that lack certain elements that preliminary results suggest are key features of the epigenetic regulation of these genes. Many questions surround the genetics of Autism and Autistic Spectrum Disorder, particularly why boys are much more susceptible to these disorders than girls. One hypothesis suggests that a special group of genes, known as imprinted genes, on the X chromosome may be an important contributing factor. X-linked imprinted genes have only recently been discovered, and it is important to gain an understanding of the role these genes play in brain development and how they are regulated.